We used Tyr c-2J/c-2J as a model for OCA1a. These mice are white with pink eyes due to a missense mutation in tyrosinase that is null at the protein level. We used Tyr c-h/c-h (Himalayan) mice as our model of OCA1b. These mice have an off-white coat color, reduced ocular pigmentation and pigmentation in their extremities due to a mutation that produces a heat-labile form of tyrosinase. We successfully obtained independent grant funding from the Blind Childrens Center for our pilot experiments. Nitisinone treatment resulted in a 6-fold and a 4-fold increase in steady-state plasma tyrosine concentrations in Tyrc-2J/c-2J and Tyrc-h/c-h mice, respectively. After one month of nitisinone treatment, C57BL6-Tyr c-h/ch mice, but not C57BL6-Tyr c-2J/c-2J mice, showed a visible increase in coat and iris pigmentation. Neither vehicle-treated group showed any change in pigmentation. (Because pigment is preferentially deposited in growing hair, a patch of each mouses coat was shaved immediately prior to initiating nitisinone treatment.) Electron microscopy studies revealed a statistically-significant difference in the number of pigmented (stage III and IV) melanosomes in the RPE, choroid and iris of treated C57BL6-Tyr c-h/ch mice. No difference was observed in C57BL6-Tyr c-2J/c-2J mice or in vehicle treated mice. This work is currently being prepared for a manuscript to be submitted to Science Translational Medicine. Preliminary studies indicate that treatment of pregnany Tyr c-h/c-h females leads to an increase in pigmentation of pups when they are born.
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